Cyclophosphamide and Anti-thymocyte Globulin Followed By Methotrexate and Cyclosporine in Preventing Chronic Graft-Versus-Host Disease in Patients With Severe Aplastic Anemia Undergoing Donor Bone Marrow Transplant

Fred Hutchinson Cancer Center (FHCC)

Status and phase

Completed

Phase 2

Conditions

Aplastic Anemia

Treatments

Procedure: allogeneic bone marrow transplantation

Other: laboratory biomarker analysis

Drug: cyclophosphamide

Biological: anti-thymocyte globulin

Other: flow cytometry

Drug: cyclosporine

Genetic: polymorphism analysis

Genetic: DNA analysis

Drug: methotrexate

Study type

Interventional

Funder types

Other

NIH

Identifiers

NCT00343785

P01HL036444 (U.S. NIH Grant/Contract)

NCI-2010-01781 (Registry Identifier)

2054.00

Details and patient eligibility

About

This clinical trial is studying how well giving cyclophosphamide together with anti-thymocyte globulin followed by methotrexate and cyclosporine works in preventing chronic graft-vs-host disease (GVHD) in patients with severe aplastic anemia undergoing donor bone marrow transplant. Giving low doses of chemotherapy, such as cyclophosphamide, before a donor bone marrow transplant helps stop the growth of abnormal cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune system and help destroy any remaining abnormal cells. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving anti-thymocyte globulin before and methotrexate and cyclosporine after transplant may stop this from happening

Full description

PRIMARY OBJECTIVES:

I. Minimize the incidence of chronic GVHD by restricting the transplanted marrow dose to 2.0-2.5 x 10^8 nucleated cells/kg.

SECONDARY OBJECTIVES:

I. Engraftment and overall survival.

OUTLINE:

CONDITIONING REGIMEN: Patients receive cyclophosphamide intravenously (IV) on days -5 to -2 and anti-thymocyte globulin IV over 4-10 hours on days -4 to -2.

TRANSPLANTATION: Patients undergo allogeneic bone marrow transplantation on day 0.

GVHD PROPHYLAXIS: Patients receive methotrexate IV on days 1, 3, 6, and 11 and cyclosporine IV over 1 hour or orally (PO) twice daily on days -1 to 50, followed by a taper until 6 months after grafting.

After completion of study treatment, patients are followed up at on day 180, 1 year, 1.5 years, 2 years, 3 years, and yearly thereafter.

Enrollment

21 patients

Sex

All

Ages

Under 65 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Any patient who has aplastic anemia with marrow failure involving 2 of the three following criteria: granulocytes < 500/uL; a corrected reticulocyte count of < 1%; platelet count of < 20,000/uL
Availability of an human leukocyte antigen (HLA)-matched family member
DONOR: Family member who is HLA-matched
DONOR: If more than one HLA-matched family member is available, priority will be given to a donor who is genotypically HLA-identical, of appropriate cytomegalovirus (CMV) serology, ABO compatible, and, in case of a female donor, non-parous

Exclusion criteria

Severe disease other than aplastic anemia that would severely limit the probability of survival during the graft procedure:
- Patients who have developed clonal cytogenetic abnormalities or myelodysplastic syndrome (preleukemia)
- Patients with Fanconi's anemia
- Aplasia secondary to radiation or cytotoxic chemotherapy
- Patients with paroxysmal nocturnal hemoglobinuria who have not developed aplastic anemia
Severe organ toxicities:
- Cardiac insufficiency requiring treatment or symptomatic coronary artery disease;
- Severe hypoxemia , partial pressure of oxygen (pO2) < 70 mm Hg, with decreased diffusion capacity of carbon monoxide (DLCO) < 70% of predicted; or mild hypoxemia, pO2 < 80 mm Hg with severely decreased DLCO < 60% of predicted;
- Impaired renal function (creatinine > 2 times upper limit of normal or estimated creatinine clearance < 60 ml/min)
Fungal infections with radiological progression after receipt of amphotericin B or active triazole for greater than 1 month
Human immunodeficiency virus (HIV)-positive patients
Females who are pregnant or breast-feeding
DONOR: Donors who have increase anesthetic risk and are not able psychologically and medically to tolerate the procedure
DONOR: HIV-positive donors

Trial design

Primary purpose

Treatment

Allocation

N/A

Interventional model

Single Group Assignment

Masking

None (Open label)

21 participants in 1 patient group

Treatment (conditioning regimen, transplant, GVHD prophylaxis)

Experimental group

Description:

Patients receive a conditioning regimen comprising cyclophosphamide IV on days -5 to -2 and anti-thymocyte globulin IV over 4-10 hours on days -4 to -2. Patients undergo allogeneic bone marrow transplantation on day 0. Patients then receive GVHD prophylaxis comprising methotrexate IV on days 1, 3, 6, and 11 and cyclosporine IV over 1 hour or PO twice daily on days -1 to 50, followed by a taper until 6 months after grafting.

Treatment: